works and

Isopropanol exposure: environmental and biological monitoring in ^a printing works

F BRUGNONE, L PERBELLINI, PAPOSTOLI, MBELLOMI,AND D CARETTA

From theIstituto di Medicina delLavoro, Universitadi Padova PoliclinicodiBorgoRoma,37134Verona, Italy

ABSTRACT

Occupational

exposureto

isopropanol

was

studied in 12 workers by testing environ- mental air, alveolar air,

venous

blood, and urine during their work shift. Isopropanol, which

ranged

in environmental air

between 7 and

645 mg/m3,

was detected

in

alveolarair, where

it ranged between

4

and 437 mg/m3, but

not

in blood

or

in urine. Alveolar isopropanol

concentra-

tion (Ca)

was

significantly correlated with environmental isopropanol concentration (Ci)

at any

time of

exposure.

The value of the arithmetical Ca/Ci ratio

was

0-418 (SD 0-101). Acetone, which

isa

metabolite of isopropanol,

was

found in alveolar air, blood, and urine in concentrations

thatwere

higher during

exposurethan

before. Alveolar and blood

acetone

concentrations

were

highly correlated with alveolar isopropanol concentrations

atany

time

duringexposure.

Acetone ranged between 0-76 and 15-6 mg/i

in

blood, between

4

and 92 ,ug/1

in

alveolar air, and between 0-85

and

53-7 mg/i

in

urine. Alveolar (Ca) and blood (Cb)

acetone

concentrations

were

highly correlated (r

=

0-67),

with a

Cb/Ca ratio of 101. Alveolar isopropanol uptake ranged between

0-03 and 6-8

mg/min and

was

highly correlated with environmental isopropanol concentration (r

=

0.92). During

exposure, acetone

eliminated by the lungs

ranged

between 20

and

273

mg

in

seven

hours and

in

urine between 0'3

and

9-6

mg

in

seven

hours. Acetonuria

was

higher the

next

morning

than at

the end of

exposure.

Isopropanol is a solvent widely used in industry and in the home and it was used for tepid sponging in feverishchildren' beforeitwasknowntobe respons- ible for the potentiation of hepatic and renal toxicity caused by haloalkanes.2-4 It is also suspected of being a carcinogenic agent after the discovery of an abnormal incidence of paranasal and sinus cancers in employeesmanufacturingisopropylalcohol.5The uptake and metabolism of isopropanol after inges- tion has been studied in man6 and

animals,7-"'

but the uptake of isopropanol from the lung and its metabolism in man have not yet been clearly eluci- dated. The present study wascarried out on a group ofworkersexposed to isopropanol with the aim of examining the uptake of isopropanol from the lung underindustrial conditions.

Materialsand methods

We studied the occupational exposure to isop- ropanolin 12workers employed ina printingworks

Received17 May 1982 Accepted23July 1982

by testing environmental air, alveolar air, venous blood, and urine. For each worker we took nine samplesof environmentalair,ninesamplesof alveo- larair, five samples ofvenousblood, and threesam- plesof urine.

Airsamples

Airsamples, whichwere allinstantaneous,'213 were collectedbefore thestartof the workshift,after the first half hour, and then hourly during the seven hoursof the whole afternoon work shift. Each alveo- larairsamplewascollectedsimultaneouslywithone environmental air sample. Alveolar Ventilation

(VA)

wasmeasured on two or moreoccasionsdur- ing the work shift.'2

Blood samples-Blood samples were collected before exposure, after the first hour, and then every twohoursuntil theendofwork.Each bloodsample was collected simultaneously with one alveolar air sample. The blood samples, which were put in glass vials, were analysed by ahead spacetechnique.

Urine samples-Urine samples were collected before exposure, after the end ofwork,andthenext

morning.^Ahead spacetechniquewasusedtoanal- ysethespecimens.

160

The sampleswerecollectedonfourdifferent days, examining three workers aday.

The concentration of isopropanol andits metabo- liteacetoneweremeasured in all the air,blood,and urine samples using gas chromatography. For the analyses a Perkin-Elmer mod F 17 gas chromato- graph with FID ^was used: column 2 m x 3 mm

outside diameter (steel column), packed with Car- bowax 1500 0.2% on Carbopack C 80-100 mesh;

temperature: injector and detector 200°C, oven

90°C; carrier gas: nitrogen; flow rate: 20 m/min.

Beforeanalysis all air sampleswerekeptatatemp- erature of 60°C and blood and urine samples ^at 370C.

Results

Isopropanol was detected in environmental and alveolarairsamplescollected duringthewhole work shift, butinnoother air samplesnorinanybloodor

urine samples. The concentration of isopropanol rangedbetween 8 and

647,ug/l

inenvironmental air and between 3 and 439 ,ug/l in alveolar air during the work shift. Table ¹ shows the individual values ofisopropanol concentration in environmental and alveolar air.

At each sampling time studied during the work shift, a good correlation was found between the environmental and alveolar isopropanol concentra-

tion(fig 1).Consideringallthe datacollectedatthe variousintervals,the correlation between the alveo- larandenvironmental concentrations of isopropanol

washighlysignificant (fig 2). The slope of theregres-

sion line shown in fig 2suggeststhatthemeanalveo- lar concentration of isopropanol corresponds to 53.9% of the environmental concentration.

Figure 3 shows the individualandmeanvaluesof the arithmetical ratios between the alveolar (Ca) and environmental (Ci) concentrations of iso- propanol (Ca/Ci). According to this, over 50% of the individualvalues of Ca/Ci ratios fall between 0 3 and 05.

The mean value of the arithmetical Ca/Ci ratio, equalto0-418,is lower than thatgiven bytheslope of the regressionline in fig2 (0-539).

Acetonewasdetectedinall thesamples of alveo- larair, blood, andurine collected. Before the work shift the mean acetone concentration was 3-7 ,tg/l (SD 3-8) inalveolarair,1-4mg/l (SD 0.5) in blood, and 3-9 mg/l (SD 7-6) in urine (table 2). Acetone

was detected in environmental air samples during the work shift only in the case of the first three workerslistedinthe tables, whowereexposedtothe highest concentrations of isopropanol (table 1).The

meanacetoneconcentrationwas 13

gg/l

(SD 9), 18

gg/1

(SD 18), and 15 ,ug/l (SD 12) in the atmos-

phere of the work place of the first, second, and third workers respectively. By comparison with these environmental acetone concentrations, the firstthree workers showedamean alveolaracetone concentration (table 3) of 38

gg/l

(SD 18), 50,ug/l (SD 29), and 41 ,tg/l (SD 16). These figures show that,asregards thefirstthreeworkers,acetonecon-

centration was higher in alveolar than in environ- mental air. During the work shift, acetone ranged between3 and93,tg/1 inalveolarair,0-76 and 15-6 Table 1 Isopropanol concentrations (,ugll) in environmental(Ci)and alveolar(Ca) air andalveolarventilation(VA)

Case VA Timesof the workshift(hours)

No Ilmin

0-5 1 2 3 4 5 6 7 , SD

1 11-3 Ci 591 581 419 396 620 460 526 352 493 100

Ca 247 294 247 184 272 259 280 267 256 33

2 11-9 Ci 479 550 369 459 620 539 526 278 478 109

Ca 408 274 271 141 290 259 333 181 270 83

3 95 Ci 544 647 419 531 343 544 266 467 470 123

Ca 439 364 285 282 266 220 138 184 272 96

4 12-9 Ci 167 114 123 69 63 59 67 128 99 40

Ca 44 55 45 32 18 25 29 46 37 13

5 12-8 Ci 212 140 187 136 51 64 129 253 146 69

Ca 101 58 70 58 15 28 35 64 53 27

6 15-6 Ci 268 155 189 129 79 80 81 9() 134 68

Ca 105 82 70 57 30 25 29 29 53 30

7 13-6 Ci 182 256 364 152 81 99 234 287 207 97

Ca 56 105 112 62 12 36 35 95 64 36

8 13-3 Ci 170 220 301 167 80 113 260 266 197 78

Ca 37 77 80 57 13 20 84 88 57 30

9 16-9 Ci 177 208 487 182 56 65 242 226 205 133

Ca 51 75 160 45 25 24 27 143 69 54

10 14-6 Ci 26 14 18 35 21 32 - - 24 8

Ca 6 6 5 20 12 14 - - 10 6

11 13-1 Ci 10 10 15 8 20 28 - - 15 8

Ca 5 5 3 5 6 17 - - 7 5

12 11-9 Ci 25 8 16 36 40 27 - - 25 12

Ca 6 5 6 8 18 11 - - 9 5

Brugnone, Perbellini, Apostoli, Bellomi, Caretta

Slope0699 0

400-

200

0 5 h

200 400 600

Slope0 535

400-

200

lst h

200 400 600

Slope: 0 512

400-

200

2ndh 20

. 6 600

Slope 0 500

*Si 4th h

200 400 600

Slope0483

.0 5thh

200 400 600

Slope:0647

- */ 6thh

y=0-539 x-16 r=0-92;n=90 p<0001

0

0 0

0.0

0;,

200 400

Environmental concentration(lg/l) 600

Fig 2 Correlationbetween alveolar(Ca) and environmental(Ci)concentrationsofisopropanol; all individualdata.

30 -

200 400 600

Slope:0519

20-

0

z 10-

0 t

*1W 7th h

200 400 600 200 400 600

(pg/1) Cj (pg/I) Ci

Fig 1 Correlations between alveolar (Ca) and environmental(Ci)concentrationsofisopropanolatthe varioustimesstudied:

/2 h: Ca=0*699Ci-41;r= 0*90;n= 12;p<0001 1st h:Ca=0-535Ci- 13;r=O099;n= 12;p<0O001 2ndh: Ca=0-512 Ci ^- 9;r= 083;n= 12;p<0-001 3rd h:Ca=0449Ci - 7;r= 095;n= 12;p< 0.001 4th h:Ca=O500 Ci- 5; r= 0-96;n= 12;p<0-001 5th h: Ca=0*483Ci- 7;r= 0-98;n= 12;p<0001 6th h: Ca=0-647 Ci -58;r= 093;n= 9;p <0O001 7th h:Ca=0519 Ci- 13;r= 0-75;n= 9;p<0-05.

M= 0418 SD= 0-101 Median=0.405

n=90

r r- I. . .-- r I I I

0.1 0.3 0.5 0.7 0.9

Distribution ofCa/Ciratio Fig 3 Distribution,mean,andmedianof individual arithmetical ratios between alveolar (Ca)andenvironmental (Ci) concentrations of isopropanol (Ca/Ci).

Table 2 Resultsof biologicalmonitoringbefore, during,andafterexposure

Subject Beforeexposure Duringexposure Afterexposure

No

Alveolar Blood Urine Alveolar Blood Urine (nextmorning)

acetone acetone acetone isopropanolacetone acetone Urine

conc conc conc uptake conc conc acetoneconc

(ligll) (Agll) (Ag/l) (,uglm') (mgl7 h) (,ugll) 6"g/l) (AgIm') (Ag/l) (AgIm')

1 4 1340 500 - 1680 8200 5400 6-0 38200 39-9

2 8 2470 1470 - 1805 7192 18200 19-5 41600 49-9

3 5 630 27700 - 1410 7635 14300 22-8 53700 54-6

4 2 1490 1750 1-6 232 3435 3650 4-0 4040 2-0

5 1 1830 3190 1-7 373 3400 4590 3-0 3400 1.1

6 1 1590 1790 2-3 434 2735 4160 4-7 4150 4-6

7 3 810 500 0-3 492 4302 1800 0-9 850 0-8

8 14 770 1130 0-8 443 5012 1080 0-5 2280 1-9

9 2 1170 5420 8-6 688 3000 1950 1-4 2230 1-8

10 1 1920 800 1-4 70 2715 2180 1-1 1840 1-4

11 3 1280 1410 1-6 23 1170 920 0-7 3630 2-3

12 1 1780 1130 0-3 48 1725 1600 0-8 1540 1-0

M 3-7 1423 3899 2-1 641 4210 4986 5-4 13122 13-3

SD 3-8 539 7619 2-5 635 2330 5515 7-6 19264 21-1

162

°.400

S200

o400-

,200

o400

200

° 400

200 ISlope 0.449

400-

0 / 200-

j,tP^ 3rdh

F-1---i

r

Table 3 Acetone concentrations (,gll)in alveolar air (Ca)and in blood (Cb)

SubjectNo Timeof work shift (hours) Mean SD

0-5 1 2 3 4 5 6 7

1 Ca 11 27 39 40 58 66 27 35 38 18

Cb - 3600 - 5370 - 8210 - 15620 8200 5298

2 Ca 18 23 36 31 71 93 88 44 50 29

Cb - 3990 - 6060 - 8240 - 10480 7192 2795

3 Ca 16 36 36 61 38 58 30 56 41 16

Cb - 5740 - 11420 - 9060 - 4320 7635 3211

4 Ca 8 10 5 14 24 21 19 18 15 7

Cb - 2140 - 3680 - 4850 - 3070 3435 1136

5 Ca 8 14 15 20 23 19 15 15 16 4

Cb - 2660 - 4250 - 2850 - 3840 3400 767

6 Ca 14 11 20 19 23 11 19 13 16 4

Cb - 2420 - 3510 - 1240 - 3770 2735 1155

7 Ca 10 7 17 24 8 15 6 14 13 6

Cb - 2340 - 4190 - 3330 - 7350 4302 2168

8 Ca 10 4 10 24 14 12 68 22 20 20

Cb - 1690 - 3930 - 4150 - 10280 5012 3683

9 Ca 14 8 61 48 18 8 65 60 35 25

Cb - 2420 - 3240 - 2990 - 3350 3000 415

10 Ca 3 6 3 4 6 4 - - 4 1

Cb - 2400 - 3030 - - - - 2715 -

11 Ca 6 3 4 4 9 5 - - 5 2

Cb - 1580 - 760 - - - - 1170 -

12 Ca 4 4 3 5 9 22 - - 8 7

Cb - 1760 - 1690 - - - - 1725 -

mg/l in blood (table 3), and between 0-9 and 18-2 mg/l in urine (table 2). The concentration of acetone in urine collected from the end of work to the next morning ranged between 0 85 and 537 mg/l (table 2).

A significant correlation between the alveolar(x) and blood (y)concentrations of acetone wasfound at the first, third, and fifth hours of the work shift, but not at the seventh or before the start of work (table 4);correlation between all thedatacollected before and during the work shift is shown in fig4.

Acetoneconcentration both in alveolar air and in blood was better correlated with the isopropanol concentration in alveolar air(Ca)thanwith theisop- ropanol concentration in environmental air (Ci)or with theisopropanol difference between CiandCa.

Figure 5 shows that in the correlation with alveolar isopropanol concentration, the alveolar concentra- tion of acetone rises according to the duration of exposure. Thecorrelationbetween alveolaracetone concentration and alveolar isopropanol concentra- tion existed at all hours of the work shift studied except the sixth hour(r =

0.49).

Figure 6 showsthatblood acetoneconcentrations are related to alveolar isopropanol concentrations and rise accordingto theduration of exposure.

The elimination ofacetoneby the lungsduringthe work shift was calculated by multiplying alveolar acetoneconcentration by

VA

andtime(Ca x

VA

x

t).Atthe various hours of the work shift theacetone eliminated by the lungs, expressed as apercentage oftheisopropanol absorbed, rosegreatly

especially

until the third orfourthhour of exposure

(fig 7).

Table 4 Correlationbetween alveolar(x,,gll)and blood (y,mgll)concentrationsofacetone

Timeofexposure Noof Intercept Slope r Significance

cases

Beforeexposure 12 +1-5 -039 -0-28 NS isth 12 +1-3 +109 +0-96 p<0-001 3rd h 12 +1-3 +119 +0-80 p<0-01

5thh 9 +2-2 +82 +0-89 p<0-01

7th h 9 +6-5 +11 +0-05 NS

According to the observation that the alveolar and blood concentrations of acetone were better correlated withisopropanolinalveolar air than with isopropanol inenvironmental airoritsCi-Ca differ-

15000

12000-

9000

g

.6000

3000-

O

* Oh o1sth

*3rdh A5thh

07th h a

0 0

A

A ~~~A

A

A*p 0

CP--, 0 a o y=101x.1842

_.0= r=0-67;n=54

CP pcOOOl

A-

20 40 60

Acetonea1veolorconceotroton(,ug/l) ⁰

Fig4 Correlation between bloodandalveolar concentrationsofacetone;allindividualdatabeforeand

after^exposuretoisopropanol.

163

Brugnone, Perbellini, Apostoli, Bellomi, Caretta

90 E601-

- 3e30

30

-~ ~

⁰

>-1W

*4r, 0.5h

200 400 600

90-

E60-

9

_

a30- *

<-I

_|-4 g l1st h

.20 40. 60

90

60 S

30 a

4th h

200 400 600

Isopropanolalveolar concentration(p9ll)

90- 0

- 60-

30 ' *

2nd h * 6t h

600 200 400 600

Fig6 Correlations between bloodacetoneconcentrations andalveolarisopropanolconcentration^atvarioustimesof exposure

lsth: Ace= 8-9 Iso+ 1691;r=0-92;n=12;p<0001 3rd h: Ace=30-4 Iso+ 1853;r=0-94;n= 12;p<0-001 5thh:Ace=23-4Iso+2658;r=0-92;n= 9;p<0001 7thh: Ace=38-7 Iso+2185;r =0-69;n = 9;p<0 05.

90

60 *.

30- .0/

3rdh 7th h

600 200 400 600

Iso(mg/m3)

Fig5 Correlations between alveolaracetone concentrations(Ace) and alveolar isopropanol concentrations(Iso)atvarioustimesofexposure:

/2 h:Ace=0-023Iso+ 7;r= 0-77;n= 12;p<0-01, 1st h:Ace=0-081 Iso+ 3;^r=0-95;n= 12;p <0001, 2ndh:Ace=0-124Iso+ 3;r=0-78;n= 12;p<001, 3rd h:Ace=0-179 Iso+ 10;r=0-83;n=12;p<0-001, 4th h:Ace=0l161 Iso+ 12;r=0-91;n=12;p<0-001, 5th h:Ace=0-267Iso+ 7;r= 0-95;n= 12;p< 0-01, 6th h:Ace=0-119Iso+24;r=0-49;n⁼ 9;p=NS 7th h:Ace⁼0-162Iso+11;r= 0-68;n= 9;p<0-05.

ence,weconsideredalveolarisopropanolconcentra-

tion asthe bestindex for calculating theamountof isopropanol absorbed by the lungs. Seeing that the

mean arithmetical Ca/Ci ratio of isopropanol was

0-418 (fig 3)we calculated the isopropanol absorp- tion asfollows:

alveolarisopropanol uptake = Ca (,g/l) x RCC x

VAwith R = 1-Ca/Ci = 0-582. a/C

The individual values of isopropanol uptake per

minute are shown in fig 8, which shows that a 25-

20-

15-

('10) 10

5.

Duration ofexposure(h)

1 2 3 4 5 6 7

120 236 314 392 467 Isoproponot absorbed(mg)

716 840

Fig7 Acetone eliminatedby lungs during exposureto isopropanol expressedasmeanpercentage ofabsorbed isopropanol.

significant correlation (r = 0.92) existed between alveolar uptake and the environmental concentra- tion of isopropanol. The total amount of isop- ropanol absorbed during the whole period of the work shiftwascalculated for the individual workers by multiplying the mean absorption per minute by the timeofexposure (table 2).

The blood acetone concentrations determined during the work shift calculatedasthe mean of the four determinations made (table 2) were

significantly correlated with the total amount of

90-

E60- 3-

4130^-

t0

I 2

200 4600

90

E60

-E

" 30

4';..

200 400 Iso(mg/m3)

164

Table5 Correlation between alveolar isopropanoluptake(mgl7 h) and bloodacetoneandurine acetoneconcentrations andbetween urine and blood acetone concentrations (mgll) in nine subjects

Intercept Slope r p Alveolar isopropanol uptake(x)/blood acetone conc (y =,ug/l) 2350 3-1 0 91 <0-001 Alveolar isopropanol uptake(x)/end-exposure urine acetone conc (y = mg/l) -235 7-6 0-78 <0 05 Alveolar isopropanol uptake(x)/end-exposure urineacetone conc(y =,g/m') - 1-5 0-01 0-75 <0 05 Alveolar isopropanol uptake(x)/next-morningurine acetone conc (y=mg/l) -9904 31 7 0-92 <0-001 Alveolar isopropanol uptake(x)/next-morning urineacetone conc (y = sg/m') -12-5 0-035 0-94 <0-001 Blood acetone conc(x)/end-exposureurineacetoneconc(y= mg/l) - 3-1 1-85 0-66 <0-1 Blood acetoneconc(x)/end-exposure urineacetone conc(y= ,ug/m') - 6-3 2-7 0-69 <0 05 Blood acetone conc(x)/nextmorningurineacetone conc(y =mg/l) -28-3 9-02 0-91 <0-001 Blood acetone conc(x)/next morning urineacetone conc(y=,ug/m') -31-7 9-8 0-90 <0-001 Table 6 Total elimination of acetone bythe lungsduring

exposureandby the kidneys duringandafter exposure SubjectNo Acetoneeliminated

Bylungs (mg/7h)

1 180

2 273

3 173

4 84

5 90

6 110

7 75

8 125

9 274

10 22

11 20

12 31

Mean 121

SD 88

isopropanol absorbed during ti

(table 5). Urineacetone concen

both at the end of the work morning (table 2) were alsosig with the total isopropanol abs(

with the mean blood acetone (

during the whole work shift (ta elimination ofacetone duringt

y=0-008x-011 r=092,n=90 p<O 001

00

200 300 4C Isopropanol environentoal conc

Fig 8 Correlation between alveolar (Ca ^xR/(CalCi) ^x VA, with Ca ⁼X cqncentration (,gll),R ⁼1-CalCi 0.418)andenvironmental isopropac

Inurine(mgil 7h) 25-8

38-1

turned out to be many times higher than the total amount of acetone eliminated in urine both at the end of exposure and the next morning (table6).

Discussion

42-3 ISOPROPANOL IN ENVIRONMENTAL AND

219

ALVEOLAR AIR

4-8 Our data on the alveolar concentration of isop- 09 ropanol show that a highly significant correlation

1-31-7 existed with environmental isopropanol concentra- 1-3 tion at all the times of exposure (fig 1). The ratio

09

between alveolar and environmental concentration 103 (Ca/Ci)was notaffectedby the duration of exposure 156 (fig 1), environmental concentration (figs2 and 3), or alveolar ventilation. The observation that the he whole work shift mean and median value of the arithmetical isop- itrations determined ropanolCa/Ci ratioare0*418 and 0*405respectively shift and the next and that more than 50% of the individual Ca/Ci

;nificantly

correlated ratio values fall between 0-3 and 0-5 (fig 3)suggests orbed (table 5) and that thevariability of the Ca/Ci ratiomightreason- concentration found ably fall in the region of these two values. This ble 5).The alveolar hypothesis is suggested by the fact that we used he whole work shift instantaneous samples and that alveolar air cannot instantaneously reflect momentary variations in environmental air but needs alapse of time for the wash in or wash out of the alveoli if there is any variation in the atmosphere. On the basis of the finding that, despite our instantaneous sampling technique, a correlation existed between alveolar andenvironmental concentration,it seemsconceiv- 0.. * . able that theabove mentioned values

might

express . *./ * the actual value of the

isopropanol

Ca/Ci ratio. In ourexperience'3 inthe alveolar airof workers each

* inhaled solvent reaches a concentration that, with

*o

environmental concentration,showsaratio (Ca/Ci) characteristic of the solvent under consideration.

Follandetal, 14 who studied 13 workers occupation- ally exposedtoisopropanol, reported environmental iO 6(g500 0 and alveolar data according to which the iso-

:entration(ffg/m3) propanol Ca/Ci ratioturns out to be between 0-247 isopropanol uptake and 0*400. The assessment of the Ca/Ci ratio is of alveolar isopropanol basic

importance

because from it we can arrive at

=0582, Ca/Ci = alveolar retention (Retention (R) = 1-Ca/Ci) and ,zolconcentration. then estimate alveolaruptake

(R

x VA x

Ci).

165

166

ISOPROPANOL IN BLOOD

Blood isopropanol concentrations have been meas-

ured in casesofacute poisoning in man. Adelson'5 foundnocorrelation betweentheseverity of poison- ingandthe blood level ofisopropanol, whichranged in all his casesbetween 1-3 and2-0 g/l. Kingetall6 foundabloodisopropanolconcentration of 4.4g/l in

a man who swallowed about a litre of "rubbing alcohol" in 10 minutes, 45 minutes before his admissiontothe hospital. Lahameta19 and Lahamet all' detected isopropanol in the blood of rats

exposed to environmental concentrations of iso- propanol ranging from 500 ppm (1225 mg/m3) to

8000ppm (18 600 mg/m3). The blood isopropanol concentrations were 30 and 503 mg/l after four hours of exposure to 1225 and 18 600 mg/m3 respectively. The simultaneous determination of

acetone in rats' blood showed a ratio between acetone and isopropanol in blood that wasthreein the lowest exposure (500-1000 ppm) and unity in the highest exposure (8000 ppm).

Our data show that the firstthree workers listed in the tables were exposed to a mean environmental concentration of isopropanol corresponding to

470-493 mg/m3 (table 1), which is about half the threshold limit value (980 mg/m3 by ACGIH, 1981). In none of these three workers, norin any

others, ^{were we} able to detect isopropanol in the bloodorurine. Themeanbloodacetoneconcentra- tion (table 2)inthese firstthree workerswas7192- 8200,ug/1 withrangesinindividual testsfrom 3600

to 15 620,g/l. Extrapolating from data on rats910

we would have expected a blood isopropanol con-

centration of 1-2-5-2mg/l-that is,one-third of the blood acetone values (3600-15620 ,g/l). Our detectablelimitforisopropanol inblood was1 mg/l andso we canconcludethatunder the conditions of

exposure we studied, the ratio of acetone to iso- propanolin blood should be higherthanthree. Our inability to detect isopropanol in blood is possibly because the apparent volume of isopropanol dis- tribution in the human body is so large that the resultant blood concentration is lower than our

technical limit of detection.

ACETONE CONCENTRATIONS

The chief metabolite of isopropanol is acetone, which maybedetected inthe urine after onehour and in expired air within 15 minutes.6 High ^con- centrations of acetone in the blood of people poisonedwithisopropanolwerereported byGlasser etal'7; Follandetall4reported ^an alveolaracetone concentration of 46 and

18,ug/1

inworkersexposed

to an environmental isopropanol concentration of 1000 and 343 ,ug/1 respectively. Our data on acetonedetermination inworkers before thestartof

isopropanolexposure showed a concentration of 3-7 ,ug/l (SD 3.8) in alveolar air, 1-4 mg/l (SD 0.5) in blood, and 3-9 mg/l (SD 7-6) in urine. Wigaeuset al'8 reported that physiological concentrations of acetone in alveolar air were 1-7 ,ug/l (SD 0.5), in blood 1*3 mg/kg (SD 0.6), and in urine 1*4 mg/kg (SD 1.1); the endogenous levels of blood acetone we found were similar. On the other hand, the concentrations of acetone in the urine and in the breath before exposure differ. We now know that thethird worker(table 2) had workedan overtime shift thatfinishedabout 10 hours beforeourexami- nation. Thisexplains his high urine acetone concent- ration (27.7 mg/l) before exposure (table 2).

It is well knownthat the alveolar concentration of acetone is related to blood acetone concentrations and that the blood/air partition coefficient of acetoneplaysadecisivepartinestablishingitscon- centration inblood and alveolar air. The blood/air partition coefficient, known also as the solubility coefficient in blood, was found in experiments in vitro to range between 218 and275.18-21 In healthy men with an endogenous blood acetone concentra- tion of 1-3 mg/kg and an endogenous alveolar acetoneconcentration of1-7

gg/l

the blood/airparti- tion coefficient is 765.18 On theother hand, in volun- teers with different levels of exposure the acetone solubility coefficient ranged from 30 to 100 during exposure.20 In the same experiments the solubility coefficient ranged between 400 and 340 after the endof exposureduring the four hours of the elimi- nation phase studied.Previously we had found in a group of workers exposed to acetone in factories a solubility coefficient of 114.19 In the present inves- tigation we found, on the basis of the slopes of the regression lines, a blood/air partition coefficient of acetone equal to 109, 119, and 82 atthe first, third, and fifth hours of exposure respectively (table 4).

Considering all thedatatogether(fig4),the solubil- ity coefficient turned out to be equal to 101, which is similar to thatof 114 which wefound previously in workers exposed to acetone. Statistical analysis showed thatagoodcorrelation between the alveolar concentration ofacetone andisopropanol existedat all the times except at the sixth hour of the work shift, when the correlation coefficient turned out to be 0*49 (fig 5). A correlation coefficient between 0-68 (seventh hour)and0-95 (fifthhour) was found atallthe other hours.Figure 5 clearly showsthat the alveolar concentration of acetone, during exposure, rises not only as a function ofalveolar isopropanol concentrationbut alsoas afunction oftheduration of exposure. According tothe slopes of the regres- sion lines reported infig5 itis clear thatthe alveolar acetone concentration as a percentage of alveolar isopropanol concentration rises from 2-3% at the

first half-hour to 26-7% atthe fifth hour ofexpos- ure. Asregards the correlations in fig 5, it is worth emphasising that the slopes were very similar- 0-179, 0*161, and 0.162 at the third, fourth, and seventh hours respectively. Despite the resultatthe fifth hour (slopes ⁼ 0-267), these figures seem to suggestthat thealveolaracetoneconcentration,as a

function ofalveolar isopropanol concentration,does notvary after the third hour of thework shift.This suggests that a steady state between the uptakeof alveolar isopropanol and its metabolism to acetone

should be reached within three hours ofexposure.

At all the sampling times studied, a significant correlation (fig 6) was again found between blood acetone concentration and alveolar isopropanol concentrations. The correlation coefficients were

0*92, 0*94, 0-92, and 0-69 respectively at the first, third, fifth, and seventh hours of the work shift. The slopes at the third, fifth, and seventh hours were

similar, 30-4,23-4, and 38-7 respectively, compared with theoneatthefirst hour of the work shift, which

was8-9. These resultssupportthe view thatasteady

state condition exists after the thirdhour of^expos-

ure.

ISOPROPANOL UPTAKE

Since alveolarconcentration isanexpression oftime integrated exposure, we preferred to calculate the alveolar isopropanoluptake byusingtheindividual values of alveolar isopropanol concentration (jug/l) determinedatthe various hours ofexposure rather thantheenvironmental isopropanol concentrations.

This isin accordance with the observation that the

acetone concentration determined, both in the alveolar airandinthe bloodofworkers exposedto

isopropanol, wasbetter correlated with isopropanol in alveolar air than with isopropanol concentration inenvironmental air. The individual dataonalveo- larisopropanol uptake (mg/min) calculatedasmen-

tioned above-that is, starting from the alveolar concentration of isopropanol (ug/l)-were significantly correlated with environmental iso- propanol concentrations (fig 8). On the basis of the slope of the regression line in fig 8,itappears that theamount of isopropanol contained in eight litres of environmental air was absorbed, on average, everyminutebythelungs.Inotherwords,itmaybe said that themeanalveolar clearanceofisopropanol

was equal to eight litres of environmental airper

minute. The alveolar uptake of isopropanol calcu- lated for the seven hours of the work shift ranged between 232 and 1805^mg (in thefirstnine workers listed in table2). The bloodacetoneconcentrations inthese nineworkers determinedasthemeanof the four determinations carried out during the work shiftweresignificantlycorrelated withtheamountof

isopropanol absorbed during the seven hours (r = 0 90,table 5). Fromthiscorrelation, it may be esti- mated that 1 g of isopropanol absorbed in seven hoursgives a mean blood acetone concentration of about 5 5 g/l.

ACETONE ELIMINATION

An examination of the urinary acetone concentra- tions at the endof exposure and the nextmorning showsthatboth the concentration and the excretion rateof acetone werehigherthenextmorningthanat the end of exposure (table 2). Some acetone con- centrations the morningafter exposurewere better correlated with the seven-hour alveolarisopropanol uptake (table 5:r = 0-92-0-94)thanwerethecon- centrations atthe endof the work shift (r = 0*78- 0.75).From fig7it may beseenthat themeanlung acetone elimination as apercentageof the alveolar isopropanol absorbed rises quickly within the first three hours and slowly thereafter. On the other hand, table 7 shows that in each individual worker the acetoneeliminated by thelungs,expressedas a percentage of the alveolar isopropanol absorbed, varied accordingtothelevel ofexposure. Itwasthe lowest (10-7-15-1%)in thefirst threeworkers,who wereexposed to thehighest isopropanolconcentra- tions (table 1: 470-493

mg/m3),

and

proportion-

ately higher (15.2-39-8%) in the other workers, who were exposed to the lowest isopropanol con- centrations (table 1:99-207mg/m3).Intable 7 the clearance ofacetonefrom thelungandrenalclear- ance are reported. The clearance of acetone from thelung, except in the last workerlisted,showed a narrow range (41-97 ml/min). The renal clearance ofacetone,ontheotherhand,showedavalue rang- ing between 0-1 and 3 ml/min, 30 or more times lower than that of clearance from the lung. An examination of the data in table 7 suggests that Table 7 Eliminationofacetoneby thelungsand kidneys Subject Alveolar* Pulmonaryt Renalt

No acetone clearance of clearance of elimination acetone(ml/min) acetone(milmin)

1 10-7% 52 0-7

2 15-1% 90 2-7

3 12-3% 54 3-0

4 36-2% 59 1-2

5 24-1% 63 1-5

6 25-3% 97 1-8

7 15-2% 41 0-2

8 28-2% 59 0-1

9 39-8% 217 0-5

*Acetone eliminated by lungs as percentage of isopropanol absorbedduringworkshift.

tAcetone eliminatedby lungsduringwork shift dividedbyblood acetoneconcentrationasmeanof four determinationscarriedout

duringworkshift.

tAcetone eliminatedinurineduringworkshift dividedbyblood acetoneconcentrationas meanof four determinationscarriedout

duringwork shift.

elimination of acetone in alveolar air in terms of percentage values (10.7-39.8%) depends inversely

onthe level ofisopropanolexposure,while interms ofpulmonaryclearance itseems tobeindependent of the level of isopropanol exposure (pulmonary clearance between41 and 97ml/minineightoutof the nine workers tested). Our findings,whichshow that kidney excretion ofacetone islow, agree with the results reportedinmenexposedtoacetone'8and with other studies22 indicatingthattherenalexcre-

tion ofacetone occursby simplediffusion.

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